title: Forcing thermodynamically unfolded proteins to fold.
abstract: A growing number of biologically important proteins have been identified as fully unfolded or partially disordered. Thus, an intriguing question is whether such proteins can be forced to fold by adding solutes found in the cells of some organisms. Nature has not ignored the powerful effect that the solution can have on protein stability and has developed the strategy of using specific solutes (called organic osmolytes) to maintain the structure and function cellular proteins in organisms exposed to denaturing environmental stresses (Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., and Somero, G. N. (1982) Science 217, 1214-1222). Here, we illustrate the extraordinary capability of one such osmolyte, trimethylamine N-oxide (TMAO), to force two thermodynamically unfolded proteins to fold to native-like species having significant functional activity. In one of these examples, TMAO is shown to increase the population of native state relative to the denatured ensemble by nearly five orders of magnitude. The ability of TMAO to force thermodynamically unstable proteins to fold presents an opportunity for structure determination and functional studies of an important emerging class of proteins that have little or no structure without the presence of TMAO.
authors.affiliation: Department of Human Biological Chemistry and Genetics, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, Texas 77555-1052, USA.
authors.forename: I
authors.initials: I
authors.lastname: Baskakov
authors.forename: D W
authors.initials: DW
authors.lastname: Bolen
mesh_terms: D008744:Methylamines / Q000494:pharmacology*; D008836:Micrococcal Nuclease / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D008956:Models, Chemical; D009154:Mutation; D009997:Osmotic Pressure; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D006163:Ribonuclease T1 / Q000737:chemistry* / Q000187:drug effects; D013816:Thermodynamics
chemical_list: D008744:Methylamines; D006163:Ribonuclease T1; D008836:Micrococcal Nuclease; C005855:trimethyloxamine